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CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy

Primary Purpose

Hematopoietic/Lymphoid Cancer, Adult Acute Lymphoblastic Leukemia in Remission, B-cell Adult Acute Lymphoblastic Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

CART-19

About this trial

This is an interventional treatment trial for Hematopoietic/Lymphoid Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion

Male and female subjects with CD19+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to < 2 year survival) with currently available therapies will be enrolled
CD19+ leukemia or lymphoma
ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor
Follicular lymphoma, previously identified as CD19+:
At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy
Stage III-IV disease
Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval < 1 year)
Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc)
CLL:
At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior
Less than 2 years between last chemotherapy and progression (i.e. most recent progression free interval < 2 years)
Not eligible or appropriate for conventional allogeneic SCT
Patients who achieve only a partial response to FCR as initial therapy will be eligible.
Mantle cell lymphoma:
Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT
Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...)
Relapsed after prior autologous SCT
B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT
Diffuse large cell lymphoma, previously identified as CD19+:
Residual disease after primary therapy and not eligible for autologous SCT
Relapsed after prior autologous SCT
Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of conventional allogeneic or autologous SCT
Expected survival > 12 weeks
Creatinine < 2.5 mg/dl
ALT/AST < 3x normal
Bilirubin < 2.0 mg/dl
Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy
Adequate venous access for apheresis, and no other contraindications for leukapheresis
Voluntary informed consent is given

Exclusion

Pregnant or lactating women
The safety of this therapy on unborn children is not known
Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
Uncontrolled active infection
Active hepatitis B or hepatitis C infection
Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary
Previously treatment with any gene therapy products
Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD28 costimulation
Any uncontrolled active medical disorder that would preclude participation as outlined
HIV infection

Sites / Locations

Abramson Cancer Center of The University of Pennsylvania

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

CART-19 CLL

CART-19 ALL

Arm Description

CART-19 (autologous T cells transduced with CD19 TCR-ζ/4-1BB vector) administered as an IV infusion days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity.Minimum/maximum total dose: 1.5x10^7 / 5x10^9 administered to patients with chronic Lymphocytic Leukemia (CLL) and Acute Lymphoblastic Leukemia (ALL).

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events

Secondary Outcome Measures

Overall Response Summary

Efficacy assessments for ALL were performed based on bone marrow and blood morphologic criteria and physical examination findings. The definitions for response are primarily based on the standardized response criteria defined by National Comprehensive Cancer Network (NCCN) Guidelines (NCCN, 2013 v.1). Efficacy assessments for CLL were based on lymphadenopathy, hepatomegaly, splenomegaly, bone marrow and blood morphologic and laboratory assessments. The response criteria are consistent with NCCN Guidelines Version 2.2012 CLL/SLL, which is based on the 2008 International Workshop Group on CLL (IWCLL) revisions of the original guidelines for evaluating disease response released in 1996 by the National Cancer Institute Working Group (NCI/WG).

Full Information

NCT ID

NCT01029366

First Posted

December 9, 2009

Last Updated

June 20, 2023

Sponsor

University of Pennsylvania

1. Study Identification

Unique Protocol Identification Number

NCT01029366

Brief Title

CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy

Official Title

Pilot Study of Redirected Autologous T-cells Engineered to Contain Anti-CD19 Attached to TCR and 4-1BB Signaling Domains in Patient With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma

Study Type

Interventional

2. Study Status

Record Verification Date

June 2019

Overall Recruitment Status

Completed

Study Start Date

March 17, 2010 (Actual)

Primary Completion Date

July 2015 (Actual)

Study Completion Date

May 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Pennsylvania

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a Pilot/Phase I, single arm, single center, open label study to determine the safety, efficacy and cellular kinetics of CART19 (CTL019) in chemotherapy resistant or refractory CD19+ leukemia and lymphoma subjects. The study consists of three Phases: 1) a Screening Phase, followed by 2) an Intervention/Treatment Phase consisting of apheresis, lymphodepleting chemotherapy (determined by the Investigator and based on subject's disease burden and histology, as well as on the prior chemotherapy history received), infusions of CTL019, tumor collection by bone marrow aspiration or lymph node biopsy (optional, depending on availability), and 3) a Follow-up Phase. The suitability of subjects' T cells for CTL019 manufacturing was determined at study entry. Subjects with adequate T cells were leukapheresed to obtain large numbers of peripheral blood mononuclear cells for CTL019 manufacturing. The T cells were purified from the peripheral blood mononuclear cells, transduced with TCR-ζ/4-1BB lentiviral vector, expanded in vitro and then frozen for future administration. The number of subjects who had inadequate T cell collections, expansion or manufacturing compared to the number of subjects who had T cells successfully manufactured is a primary measure of feasibility of this study. Unless contraindicated and medically not advisable based on previous chemotherapy, subjects were given conditioning chemotherapy prior to CTL019 infusion. The chemotherapy was completed 1 to 4 days before the planned infusion of the first dose of CTL019. Up to 20 evaluable subjects with CD19+ leukemia or lymphoma were planned to be dosed with CTL019. A single dose of CTL019 (consisting of approximately 5x10^9 total cells, with a minimal acceptable dose for infusion of 1.5x10^7 CTL019 cells) was to be given to subjects as fractions (10%, 30% and 60% of the total dose) on Day 0, 1 and 2. A second 100% dose of CTL019 was initially permitted to be given on Day 11 to 14 to subjects, providing they had adequate tolerance to the first dose and sufficient CTL019 was manufactured.

Detailed Description

Primary objectives: 1. To evaluate the safety and feasibility of a single target dose of 5 times 10e9 total cells, acceptable range of 1.5 times 10e7 to 5 times 10e9 total cells comprised of autologous CART-19 cells that express the TCR zeta and 4-1 BB costimulatory domain. Secondary objectives: Proof of mechanism: determine if 2nd generation CAR expressing 4-1BB costimulation domains have improved persistence in patients. Proof of concept: determine the effects of CART-19 on CD19 expression in vivo. Proof of bioactivity: Evaluate changes in systemic soluble immune factors in patients Proof of bioactivity: Evaluate impact of CART19 treatment on tumor burden Explore whether CART-19 cells retain anti-tumor activity in vivo. Determine if host immunity develops against CART-19. Characterize the relative subsets of CART-19 T cells (Tcm, Tem, and Treg). Describe survival and response rates

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hematopoietic/Lymphoid Cancer, Adult Acute Lymphoblastic Leukemia in Remission, B-cell Adult Acute Lymphoblastic Leukemia, B-cell Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Refractory Chronic Lymphocytic Leukemia, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Chronic Lymphocytic Leukemia, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

26 (Actual)

8. Arms, Groups, and Interventions

Arm Title

CART-19 CLL

Arm Type

Experimental

Arm Description

Arm Title

CART-19 ALL

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

CART-19

Intervention Description

Autologous T cells purified from the peripheral blood mononuclear cells of subjects, transduced with TCR-ζ/4-1BB lentiviral vector, expanded in vitro and then frozen for future administration.

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events

Time Frame

5 years

Secondary Outcome Measure Information:

Title

Overall Response Summary

Description

Time Frame

5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Male and female subjects with CD19+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to < 2 year survival) with currently available therapies will be enrolled CD19+ leukemia or lymphoma ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor Follicular lymphoma, previously identified as CD19+: At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy Stage III-IV disease Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval < 1 year) Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc) CLL: At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior Less than 2 years between last chemotherapy and progression (i.e. most recent progression free interval < 2 years) Not eligible or appropriate for conventional allogeneic SCT Patients who achieve only a partial response to FCR as initial therapy will be eligible. Mantle cell lymphoma: Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...) Relapsed after prior autologous SCT B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT Diffuse large cell lymphoma, previously identified as CD19+: Residual disease after primary therapy and not eligible for autologous SCT Relapsed after prior autologous SCT Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of conventional allogeneic or autologous SCT Expected survival > 12 weeks Creatinine < 2.5 mg/dl ALT/AST < 3x normal Bilirubin < 2.0 mg/dl Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy Adequate venous access for apheresis, and no other contraindications for leukapheresis Voluntary informed consent is given Exclusion Pregnant or lactating women The safety of this therapy on unborn children is not known Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion Uncontrolled active infection Active hepatitis B or hepatitis C infection Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary Previously treatment with any gene therapy products Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD28 costimulation Any uncontrolled active medical disorder that would preclude participation as outlined HIV infection

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Noelle Frey, MD

Organizational Affiliation

Abramson Cancer Center at Penn Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Abramson Cancer Center of The University of Pennsylvania

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

31815579

Citation

Frey NV, Shaw PA, Hexner EO, Pequignot E, Gill S, Luger SM, Mangan JK, Loren AW, Perl AE, Maude SL, Grupp SA, Shah NN, Gilmore J, Lacey SF, Melenhorst JJ, Levine BL, June CH, Porter DL. Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Feb 10;38(5):415-422. doi: 10.1200/JCO.19.01892. Epub 2019 Dec 9.

Results Reference

derived

PubMed Identifier

31076448

Citation

van Bruggen JAC, Martens AWJ, Fraietta JA, Hofland T, Tonino SH, Eldering E, Levin MD, Siska PJ, Endstra S, Rathmell JC, June CH, Porter DL, Melenhorst JJ, Kater AP, van der Windt GJW. Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy. Blood. 2019 Jul 4;134(1):44-58. doi: 10.1182/blood.2018885863. Epub 2019 May 10.

Results Reference

derived

PubMed Identifier

25317870

Citation

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. doi: 10.1056/NEJMoa1407222. Erratum In: N Engl J Med. 2016 Mar 10;374(10):998.

Results Reference

derived

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CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy

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